Note: Descriptions are shown in the official language in which they were submitted.
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NEW VACCINAL ASSOCIATIONS
This invention relates to new vaccinal
associations against viral, bacterial and parasitic
pathogenic agents.
Generally, in the fields of the preparation
of human and veterinary vaccines, one tries to
prepare purified, or sub-unit, vaccines, made up
of one or several immunogenic agents of the same
kind from an infective pathogenic agent, or even
only from the immunogenic agent's antigenic determinant,
so as to obtain a well-defined protecting immune
response and also to eliminate lesser known or toxic
constituents.
As to vaccine associations, they generally
aim to unit valencies from heterologuous pathogenic
agents, or at least from different serotypes, so
as to broaden the protective spectrum, this method
being also used in the case of recombinant living
vaccines.
True, in some isolated cases, it has been
suggested to potentiate a sub-unit vaccine with
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concomitantly administrating a small amount of
the whole pathogenic agent.
W.G. LAVER and R.G. WEBSTER (Virology 69,
511-522, 1976) have shown, for the influenza virus
on hamsters and mice the potentiation of the immune
response through concomitant injection of the
untouched whole virus and the neuraminidase - hemagglutinin
sub-unit vaccine or through injection of the untouched
virus one hour before that of the same sub-unit
vaccine.
R.G. WEBSTER et al. (The Journal of
Immunology, Vol. 118, N 6, Decernber 1977, pp. 2073-
2077) later showed on hamsters and men the potentiating
effect of adding the inactivated influenza virus
to the neuraminidase-hemagglutinin sub-unit vaccine.
This virus is the whole inactivated influenza
virus, and the amount of whole pathogenic agent is
small and aimed at potentientating the protecting
effect of the sub-unit vaccine.
This invention has now shown in a surprising
way that in the case of pathogenic agents which are
very far from the influenza virus, such as notably
the herpesviridae, the association of an envelope
or wall sub-unit vaccine, i.e. immediately or easily
apparent immunogenic agents Of the same pathogenic
agents, greatly reinforces the efficiency of the
vaccination, and that this feature extends to many
pathogenic agents, including those belonging to widely
different groups such as viruses, bacteria and
parasitic agents, notably protozoa.
Aim of the invention is to significantly
reinforce the efficiency of a vaccination against
infectious diseases in animal and man.
Aim of this invention is thus a vaccinal
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association comprising a first valency comprising
an attenuated living microbial agent or a recombinant
expressing antigenic proteins or glycoproteins of
said agent, and a second valency comprising one or
several antigenic envelope or wall glycoproteins,
or an antigenic structural protein, notably of the
same serotype.
By microbial agent, in the sense of the
invention, is understood a virus, a bacterium, or
a parasitic agent belonging to a pathogenic species
and for which already exists, or may be produced,
a living or inactivated form (deleted or not) which
is immunogenic, and at least partially protecting,
or else for which there are, or there may be built,
nucleotide sequences which may be inserted in a
recombinant heterologuous microorganism to be used
as a vaccine and expressing antigenic proteins or
glycoproteins which are at least partially protecting
and encoded by such a sequence.
Among viral agents, one may notably mention,
besides herpes viruses, parvoviruses, coronaviruses,
human, porcine or equine influenza viruses, the polio-
myelitls virus and the rabies viruses.
Among bacteria one may notably mention
Brucella.
Among heterologuous microorganisms, one
may notably mention pox-viruses, for instance vaccine
or aviary pox-viruses, and herpes-viruses.
One must understand that in this invention
the second valency generally comes from the same
serotype (when different serotypes exist) as the
agent yielding the first valency, but that in some
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cases, serotypes may differ when it is avered that
there is an efficient cross protection between sero-
types.
The invention notably concerns a human
or animal herpes vaccinal association comprising
a first valency including the herpes virus in question
in the attenuated living state (deleted or not deleted)
or a recombinant expressing antigenic glycoproteins
of said virus, and a second valency comprising
one or several antigenic envelope glycoproteins,
notably of the same serotype, and possibly other
antigenic elements from said virus.
Among animal herpes, the invention
notably relates to porcine, equine, bovine,
feline and aviary herpes viruses.
Valencies may be made up of already known
vaccines for men or animals. Vaccines based on atte-
nuated living virus or vaccines based on viral sub~
units especially on envelope glycoproteins and nucleocapsides
are thus notably known.
For Aujeszky's disease ~pseudo~abies), one may for instance mention
Rhône Mérieux's Geskalone~ vaccine (France), which
is an attenuated freeze-dried living vaccine in
an aqueous or oily solvent, and the Geskypur~ vaccine,
also from Rhône-Mérieux, which is a sub-unit vaccine,
liquid or freeze-dried, with an adjuvant and made
up of purified envelope glycoproteins.
According to the invention, this vaccinal
association may be in the form of a unique preparation,
or an extemporaneous mixture or with the two valencies
separated for a separated concomitant administration.
By separated concomitant administration are meant
injections in different points of the organism in
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a reduced time interval not extendin~ beyond a few
hours and preferably a few minutes.
In the case of a ready for use preparation,
the glycoprotein valency and the valency of the
agent or attenuated virus or of recombinant are in
a solution in an aqueous or oily solvent.
Preferably, in all other cases, the
attenuated or recombinant valency is in the freeze-
dried form and the glycoprotein valency is in the
liquid or freeze-dried form.
The two valencies may be either freeze-
dried and in admixture in the same flask to be
later taken up with an aqueous or oily solvent, or
the first valency may be taken up with the second
valency initially in a liquid state in a aqueous
or an oily medium, or again each of the valencies,
freeze-dried and separated, may be taken up with
a solvent of the same nature, aqueous or oily solvent,
and then mixed together.
In the case of a separated concomitant
administration, the valencies solvents may be
aqueous, oily or respectively aqueous and oily.
The vaccinal association will preferably
be presented in a unique package.
In the case of a unique preparation, the
vaccinal association is presented in a ready to use
form. Its administration may notably be made
intramuscularly or intradermally.
In the case of an extemporaneous mixture,
the two valencies are in the freeze-dried state,
in the same flask and must be taken up with an
aqueous or oily solvent, or each valency is separately
presented and the two valencies must then be
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reunited on administration in the above described
manner. The administration route is notably intra-
muscular or intradermal.
In the case o~ a separated concomitant
administration, the two valencies are presented
separately. The glycoproteins valency may be ready
to use or, like the first valency, may be in a
freeze-dried form and must then be dissoluted before
use. The administration route is notably intramuscular
or intradermal for the valency including the attenuate
agent or virus or a recombinant whereas, for the
other valency, the administration route may be intrader~al,
intramuscular or subcutaneous.
As an herpes veterinary association, one
may mention for instance the Geskalone~-Geskypur~
association.
Naturally, the inventive association relates
to all known attenuated or glycoprotein sub-unit
vaccines. For equine, bovine, feline, and aviary
herpes (including laryngotracheitis), attenuated
living vaccines are already known and one may mention,
as examples, the following sub-unit vaccines :
- equine vaccine : PNEUMEQUINE~
(Rhône Mérieux), an equine rhinopneumonitis
vaccine ;
- bovine vaccine : IBEPUR~ (Rhône Mérieux),
a bovine infectious rhinotracheitis vaccine ;
- feline vaccine : CORIFELIN~ or LEUCORIFELIN~
(Rhône Mérieux), feline rhinotracheitis virus vaccine ;
- aviary vaccine : in~ectious laryngotrachei~is.
The invention also relates to a vaccination
proeess, notably against human or animal herpes viruses,
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comprising the concomitant administration of the
two above described valencies, mixed or separated,
via the appropriate above mentioned administration
route.
The invention will now be described more
in detail with the help of embodiment examples and in
.vivo. assay.
I. ASSAY
18 pigs were vaccinated against pseudorabies
disease. These pigs were issued from sows which were
vaccinated with the TOLVID vaccine (an attenuated
vaccine deleted for gX) (twice a year). The protocol
was the following :
- - 6 non-vaccinated pigs were used as control,
- 6 pigs were vaccinated once with the Bartha strain
as taken up in an oil-in-water Solvay adjuvant,
the vaccine title being 105-5 CCID.50 per doses,
- 6 pigs were vaccinated once with a GESKALONE gI-
dose with a title of 105 5 CCID.50 per doses,
taken up in a 2 ml GES~YP~R.
All these pigs wer con~ined together and
4 weeks after vaccination, they were all challenged
by the oronasal route with 105 5 CCID.50, this dose
being administrated thrice during 24 hours .
Serological results (seroneutralizing antibodies) :
- the control animals remain negative until the
challenge : title < 2,
- the animals which were vaccinated with the Bartha
have an average title at the challenge time between
4 and 16,
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- animals which were vaccinated with GESKYP~R/
GESKALONE :
1 animal : title 4.
1 animal : title 32
4 animals: titles 96.
Challenge :
Viral excretion parameter
Duration Title Number of
excreting animals
control 5/6 days - all animals
Bartha 2/3 days 1o2 to 3 4 out of 6
GESKYPUR/
GESKALONE 1 day hardly 2 out of 6
noticeable
One thus obtains exceptional serological
titles and challenge results.
II. EXAMPLES
1/ A unique preparation is carried out
with a Geskalone dose taken up with 2 ml Geskypur.
This preparation is ready to use and may be adminis-
trated via an intramuscular or intradermal route.
2/ One dose freeze-dried Geskalone and
one dose ready to use Geskypur are put together in
an unique package. At the time of administration,
Geskalone is taken up with Geskypur. Administration
is made intramuscularly or intradermally.
3/ Same as 2/ but Geskalone is taken up
with an appropriate aqueous or oily solvent and the
two valencies are concomitantly and separatedly admi-
nistrated vla an intradermal or intramuscular route,
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or via a subcutaneous route for Geskypur.
With the intradermal route, the two dose
volumes are preferably 0.2 ml for each valency or
for the two united valencies.
For the breeding pigs a primo-vaccination
is for instance provided with two injections at 3
or 4 week 's intervals with boosters every six months,
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